User:Robwwilliams/sandbox

Systems genetics or "network genetics" is an emerging new branch of genetics that aims to understand complex causal networks of interactions at multiple levels of biological organization. To put this in a simple context: Mendelian genetics can be defined as the search for linkage between a single trait and a single gene variant (1 to 1); complex trait analysis can be defined as the search for linkage between a single trait and a set of gene variants (QTLs, QTGs, and QTNs) and environmental cofactors (1 to many); and systems genetics can be defined as the search for linkages among networks of traits and networks of gene and environmental variants (many to many).

A hallmark of systems genetics is the simultaneous consideration of groups (systems) of phenotypes from the primary level of molecular and cellular interactions that ultimately modulate global phenotypes such as blood pressure, behavior, or disease resistance. Changes in environment are also often important determinants of multiscalar phenotypes; reversing the standard notion of causality as flowing inexorably upward from the genome. Scientists who use a systems genetics approach often have a broad interest in modules of linked phenotypes. Causality in these complex dynamic systems is often contingent on environmental or temporal context, and often will involve feedback modulation. A systems genetics approach can be unusually powerful, but does require the use of large numbers of observations (large sample size), and more advanced statistical and computational models.

Systems genetics is not really a new field and traces back to Sewall Wright's classical paper (Wright, 1921, "Correlation and Causation") that introduced path analysis to study systems of related phenotypes. Two factors have invigorated this field. The first factor is the advent of more sophisticated statistical methods including Structural Equation Modeling (SEM), System Dynamics Modeling, and Bayesian Network Modeling combined with powerful computer systems and efficient algorithms. The second factor is the relative ease with which it is now possible to acquire extensive and diverse phenotype data sets across genetic reference populations such as the BXD set of mice, the HXB set of rats, and the BayXSha lines of Arabidopsis (data are incorporated in the GeneNetwork). In the case of the BXD strains, a large research community has collectively generated hundreds of thousands of transcript phenotypes in different tissues and cells (level of expression), as well as hundreds of protein, cellular, pharmacological, and behavioral data types across a single genetic reference panel. Evaluating and modeling the associative and causal relations among these phenotypes is a major, and still relatively new area of research. Complex trait analysis and QTL mapping are both part of systems genetics in which causality is inferred using conventional genetic linkage (Li et al., 2005). One can often assert with confidence that a particular module of phenotypes (component of the variance and covariance) is modulated by sequence variants at a common locus. This provides a causal constraint that can be extremely helpful in more accurately modeling network architecture. Most models are currently static, but as the field matures, more sophisticated dynamic models will supplant steady-state models.

The term "systems genetics" was coined by Grant Morahan, October 2004, as a more general and appropriate term to use instead of "genetical genomics."